This proposal, "Pathogenesis of Functional Hypothalamic Amenorrhea," is in response to PA-9l-lOO, "Special Issues in Women's Mental Health Over the Life Cycle." Ovulatory dysfunction is the most common cause of infertility in women and functional hypothalamic amenorrhea (FHA) is the most common cause of ovulatory dysfunction. FHA is the cessation of menses in a previously eumenorrheic woman in whom organic causes have been excluded and therefore it is theoretically reversible. A constellation of neuroendocrine secretory disturbances attributable to altered hypothalamic function, including reduced LH pulsatility, have been documented. The proximate cause of FHA is insufficient GnRH secretion. The goal of this proposal is to investigate the genesis of the altered hypothalamic function, particularly the disruption of the GnRH pulse generator, so that targeted interventions can be devised. The overall hypothesis underlying this series of studies is that FHA follows a chronic and/or excessive stress response, so the two main components of the stress system, the CRH neuronal network and the locus ceruleus-norepinephrine/autonomic system, will be examined in humans and monkeys. The following specific hypotheses will be tested: (l) women with FHA have distinct cognitive and psychological characteristics that are likely to predispose to activation of the stress systems; (2) women with FHA are more reactive to behavioral challenge; (3) central neuronal systems that regulate hypothalamic function (as assessed by CSF levels) are altered in women with FHA; (4) social stress induces FHA and a constellation of neuroendocrine disturbances in monkeys similar to those seen in women with FHA; (5) pharmacological blockade of the central neuronal systems activated by social stress in monkeys prevents FHA; (6) monkeys become sensitized to repetitive social stress with regard to the development of FHA. With regard to refining our model of the pathogenesis of FHA, the monkey studies are critical to identifying causality and pharmacologic agents, while the human studies are integral to devising targeted psychosocial and/or pharmacologic interventions. We expect that the results of this proposal will lead directly to the PA-91-lOO objective of developing a "psychosocial intervention for infertility."